Covalent attachment of resveratrol to stainless steel toward the development of a resveratrol-releasing bare-metal stent.
- 作者列表："Creasey HN","Brandel EZ","Nguyen R","Bashore MJ","Jones CM
:Herein, we describe the covalent attachment of resveratrol, a naturally occurring antioxidant, to the surface of stainless-steel as a model for designing a novel bare-metal stent to treat coronary artery disease. Resveratrol has been shown to reduce oxidative stress in dysfunctional endothelial cells, and stimulate arterial healing. Resveratrol treatments, however, are limited by low water solubility, such that a localized delivery to the site of arterial narrowing via a coated stent presents a promising strategy for improving stent outcomes. Our attachment strategy utilizes zirconium vapor deposition to lay down a thin layer of zirconium oxide with labile hydrocarbon groups at the surface. Resveratrol can displace these hydrocarbons in aprotic solvent to afford a covalently attached layer of resveratrol. We evaluated the release of resveratrol under a range of pH levels, including physiological conditions (pH = 7.4 and 37 °C). Furthermore, we established that endothelial cells grown on a resveratrol-bound surface release elevated nitric oxide levels compared to controls, a key endothelial signaling molecule responsible for arterial health. These results are promising toward the development of a resveratrol-coated bare-metal stent to improve patient outcomes.
在此，我们描述了白藜芦醇 (一种天然存在的抗氧化剂) 共价附着在不锈钢表面，作为设计新型裸金属支架治疗冠状动脉疾病的模型。白藜芦醇已被证明可以减少功能失调的内皮细胞的氧化应激，并刺激动脉愈合。然而，白藜芦醇的治疗受到低水溶性的限制，因此通过涂层支架局部输送到动脉狭窄部位为改善支架结果提供了一种有希望的策略。我们的附着策略利用锆气相沉积，在表面铺设一层具有不稳定烃基的氧化锆薄层。白藜芦醇可以在非质子溶剂中取代这些碳氢化合物，以提供共价附着的白藜芦醇层。我们评估了白藜芦醇在一系列 pH 水平下的释放，包括生理条件 (pH = 7.4 和 37 ℃)。此外，我们建立了与对照组相比，白藜芦醇结合表面生长的内皮细胞释放升高的一氧化氮水平，这是负责动脉健康的关键内皮信号分子。这些结果有望开发白藜芦醇涂层的裸金属支架，以改善患者的预后。
METHODS:Aims : We sought to investigate the thrombogenicity of different DES and BMS in an in vitro system of stent perfusion. Material and Methods: The experimental model consisted of a peristaltic pump connected to 4 parallel silicone tubes in which different stents were deployed. Blood was drawn from healthy volunteers and the amount of stent surfaced -induced thrombus deposition was determined using 125 I -fibrinogen. Results: Compared to Resolute, Biomatrix and Vision, Xience was associated with the lowest amount of stent surface -induced thrombus formation, with a significant difference compared to Vision (125 I -fibrinogen median value deposition [IQ range]: 50 ng [25 -98] versus 560 ng [320 - 1,520], respectively, p<0.05), but not to other DES. In the second set of experiments Fluoropolymer -coated BMS not eluting drug was associated with a significant 3 -fold reduction in 125 I -fibrinogen deposition (245 ng [80 -300]) compared to Vision (625 ng [320 -760], p<0.05), but a 7 -fold increase compared to Xience (35 ng [20 -60], p<0.05). Finally Xience was associated with a significantly greater absorption of albumin compared to BMS. Conclusions: In an in vitro system of stent perfusion, Xience was associated with the lowest amount of stent surface -induced thrombus formation compared with Resolute, Biomatrix and Vision, with a noted synergistic effect between the fluoropolymer and the drug.
METHODS::Fibronectin-splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.
METHODS:OBJECTIVE:The goal of this study was to determine the impact of late-acquired stent malapposition (LASM) on long-term clinical outcomes in patients treated with coronary stent implantation. Approach and Results: We investigated major adverse cardiac event during 10 years after 6-month intravascular ultrasound examination using our previous studies database. A total of 732 patients treated with bare-metal stent (54 LASM versus 678 non-LASM) and 529 patients treated with first-generation drug-eluting stent (82 LASM versus 447 non-LASM), who did not have clinical event or censoring at the time of follow-up intravascular ultrasound, were included for the present analysis. major adverse cardiac event was defined as the composite of cardiac death, target vessel-related myocardial infarction, target lesion revascularization and stent thrombosis. Multivariable adjustment and inverse probability weight were performed to consider baseline differences. After multivariable adjustment, LASM was related to a greater risk of major adverse cardiac event (hazard ratio, 1.666 [95% CI, 1.041-2.665]; P=0.0333) and very-late stent thrombosis (hazard ratio, 3.529 [95% CI, 1.153-10.798]; P=0.0271) than non-LASM in patients treated with first-generation drug-eluting stent, but not in those treated with bare-metal stent. Results were consistent after inverse probability weight. Among patients with LASM of first-generation drug-eluting stent, no late stent thrombosis occurred in patients who continued to receive dual antiplatelet therapy. CONCLUSIONS:The relationship between LASM and major adverse cardiac event might depend on the type of implanted stents during the long-term follow-up, highlighting the clinical significance of polymers and drugs in drug-eluting stent system.